Dietary restriction transforms the mammalian protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific sulfhydromes. Here, we found protein persulfidation was enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking H2S producing enzyme cystathionine γ-lyase (CGL) had overall decreased tissue protein persulfidation and failed to functionally augment sulfhydromes in response to DR. Overall, we defined tissue- and CGL-dependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

硫化氢（hydrogen sulfide, H₂S）是一种具有细胞保护作用的氧化还原活性代谢物，可通过蛋白质过硫化修饰（protein persulfidation, R-SSₙH）介导信号传导。尽管目前已明确过硫化修饰对少量已鉴定蛋白质的重要性，但组织特异性巯基修饰组（sulfhydrome）谱及其相关功能的特征仍未得到充分阐明，在已知可调控硫化氢生成的条件下尤为如此。我们提出假说：饮食限制（dietary restriction, DR）可延长寿命并促进硫化氢生成，同时能够扩大组织特异性巯基修饰组的范围。本研究中，我们发现两种饮食限制干预下，年轻与老年雄性小鼠的肝脏、肾脏、肌肉及脑组织中蛋白质过硫化修饰水平均显著富集，而心脏组织中的该修饰水平则有所下降；此外，饮食限制可在众多代谢与衰老相关通路中促进蛋白质过硫化修饰。缺失硫化氢生成酶胱硫醚γ裂解酶（cystathionine γ-lyase, CGL）的小鼠，其组织内蛋白质过硫化修饰整体水平降低，且无法在饮食限制干预下功能性地扩增巯基修饰组。综上，本研究明确了组织依赖性与胱硫醚γ裂解酶依赖性的巯基修饰组特征，以及饮食如何重塑其组成，凸显了饮食限制与硫化氢对生物学过程及机体健康的广泛影响。